Hirudin is an anti-blood coagulation factor which is secreted from the salivary glands of Hirudo medicinal is. Since hirudin exhibits an anti-thrombin activity, this compound and its variants are used as anti-blood coagulation drugs.
The hirudin and most hirudin variants contain a sequence of -Asp-Gly- or -Asn-Gly- and change into succinimide compounds due to a change in this sequence with the passage of time. The succinimide compounds further change into .beta.-rearranged compounds. Because of this, even if the compounds are sufficiently purified in the production line, the purity of the compounds decreases with the passage of time due to production of the succinimide compounds and .beta.-rearranged compounds. Because the succinimide compounds and .beta.-rearranged compounds exhibit anti-thrombin activity themselves (Japanese Patent Application Laid-open No. 310788/1993), such a decrease in purity does not cause serious problems in general. However, such deterioration of the purity is not desirable when these compounds are used as drugs. Therefore, various studies have been undertaken to improve the stability of hirudin.
Examples of them include a method of adding a water-soluble salt of calcium and/or magnesium to hirudin to increase the stability of hirudin (Japanese Patent Application Laid-open No. 267877/1995), a method of adding potassium phosphate and sugar (WO 95/20399), and the like. However, these proposed methods cannot accomplish sufficiently increase in the stability of hirudin.